All publications herein are incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
ErbB4 is the least well-understood member of the family of receptor tyrosine kinases which also includes EGF receptor (EGFR/ErbB1), ErbB2/HER2, and ErbB3 (Wieduwilt, M. J., and Moasser, M. M. (2008) Cellular and molecular life sciences: CMLS 65, 1566-1584). ErbBs recognize and are activated by a suite of ligands including heparin-binding EGF-like growth factor (HB-EGF), betacellulin, and the heregulin/neuregulin family (Wilson, K. J., Gilmore, J. L., Foley, J., Lemmon, M. A., and Riese, D. J., 2nd. (2009) Pharmacology & therapeutics 122, 1-8). Ligand binding is associated with receptor dimerization, increased tyrosine kinase activity, and auto-phosphorylation on c-terminal tyrosine residues, which then provide docking sites for downstream effectors (Bublil, E. M., and Yarden, Y. (2007) Current opinion in cell biology 19, 124-134). Different ligands show distinct specificities and affinities for different ErbB receptors, and stimulate diverse dimerization patterns, signaling, and cellular responses (Saito, T., Okada, S., Ohshima, K., Yamada, E., Sato, M., Uehara, Y., Shimizu, H., Pessin, J. E., and Mori, M. (2004) Endocrinology 145, 4232-4243; Sweeney, C., Lai, C., Riese, D. J., 2nd, Diamonti, A. J., Cantley, L. C., and Carraway, K. L., 3rd. (2000) J Biol Chem 275, 19803-19807).
ErbB4 has several features which distinguish it from other tyrosine kinases, making it a unique target both in terms of signaling and potential role in human disease. It can bind both heregulin/neuregulin growth factors and a subset of EGF-family factors (Jones, J. T., Akita, R. W., and Sliwkowski, M. X. (1999) FEBS letters 447, 227-231), but at least one peptide ligand—NRG4—is exclusive to ErbB4 and does not bind ErbB1-3 (Harari, D., Tzahar, E., Romano, J., Shelly, M., Pierce, J. H., Andrews, G. C., and Yarden, Y. (1999) Oncogene 18, 2681-2689). Furthermore, ErbB4 associates with a divergent and more restricted suite of SH2-containing targets than EGFR, ErbB2, or ErbB3 (Kaushansky, A., Gordus, A., Budnik, B. A., Lane, W. S., Rush, J., and MacBeath, G. (2008) Chem Biol 15, 808-817). Thus, selective ErbB4 activation with NRG4 may elicit different cellular outcomes than stimulation with other EGF-like or heregulin family molecules.
ErbB4 is induced in colonic epithelial cells by inflammatory cytokines, and is present at elevated levels in the inflamed colonic mucosa of IBD patients (Frey, M. R., Edelblum, K. L., Mullane, M. T., Liang, D., and Polk, D. B. (2009) Gastroenterology 136, 217-226). This appears to be a compensatory protective response rather than a pathological process, as ectopic ErbB4 overexpression protects cultured mouse colon epithelial cells from cytokine-induced apoptosis in a ligand-dependent manner (Frey, M. R., Edelblum, K. L., Mullane, M. T., Liang, D., and Polk, D. B. (2009) Gastroenterology 136, 217-226; Hilliard, V. C., Frey, M. R., Dempsey, P. J., Peek, R. M., Jr., and Polk, D. B. (2011) American journal of physiology. Gastrointestinal and liver physiology 301, G338-346; Frey, M. R., Hilliard, V. C., Mullane, M. T., and Polk, D. B. (2010) Laboratory Investigation 90, 1415-1424). However, these studies, like most investigation of ErbB4 function, used shared ErbB ligands heregulin(HRG)-1β or HB-EGF, raising the question of signal specificity.
Crohn's disease and ulcerative colitis, collectively known as IBD, together affect more than 1.4 million American patients (Strober, W., Fuss, I., and Mannon, P. (2007) J Clin Invest 117, 514-521). The causes and cures of IBD remain elusive, but it is clear that a general feature of the pathology of these disorders is elevated apoptosis in the intestinal epithelium (Qiu, W., Wu, B., Wang, X., Buchanan, M. E., Regueiro, M. D., Hartman, D. J., Schoen, R. E., Yu, J., and Zhang, L. (2011) J Clin Invest 121, 1722-1732; Di Sabatino, A., Ciccocioppo, R., Luinetti, O., Ricevuti, L., Morera, R., Cifone, M. G., Solcia, E., and Corazza, G. R. (2003) Diseases of the colon and rectum 46, 1498-1507), driven by inflammatory cytokines such as TNF and IFN-γ. Thus, identifying signal transduction pathways which protect colon epithelial cells from cytokine- or injury-induced apoptosis will lead to new methods to control disease flares.
Current therapies for inflammatory bowel disease include anti-TNF therapies and steroid anti-inflammatories and are generally aimed at interrupting inflammation rather than specifically promoting mucosal healing. These therapies have shown limited effectiveness. In the instant invention, the inventor proposes alternative therapies for treating inflammatory bowel disease.
Necrotizing enterocolitis is a disease condition in which portions of the bowel undergo tissue necrosis. It is predominant in premature infants, wherein the timing of its onset is generally inversely proportional to the gestational age of the baby at birth. Current treatments include using an IV catheter to provide nutrients, antibiotic therapy to treat infections, surgery etc. Herein, the inventor provides an alternative therapy for treating necrotizing enterocolitis.